Acute Myocardial Infarction, Moderate Renal Impairment
Conditions
Brief summary
This study is a phase 2, multicenter, double-blind, randomized, placebo controlled, parallel-group study to investigate the renal safety and tolerability of multiple dose intravenous (IV) administration of CSL112 compared with placebo in subjects with moderate renal impairment (RI) and acute myocardial infarction (AMI).
Interventions
BIOLOGICALCSL_112
CSL112 is a novel formulation of apolipoprotein A-I (apoA-I) purified from human plasma and reconstituted to form high-density lipoprotein (HDL) particles.
OTHERPlacebo
0.9% weight/volume sodium chloride solution (ie, normal saline)
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Men or women, at least 18 years of age, with evidence of moderate renal impairment (an eGFR ≥ 30 and \<60 mL/min/1.73 m2) and myocardial necrosis in a clinical setting consistent with a type I (spontaneous) acute myocardial infarction (AMI).
Exclusion criteria
* Symptoms, biomarker elevation or electrocardiogram (ECG) changes other than those of the index event that are consistent with a diagnosis of AMI but are likely not due to primary myocardial ischemia * Ongoing hemodynamic instability * Planned coronary artery bypass surgery * Evidence of hepatobiliary disease * History of acute kidney injury (AKI) after previous exposure to an intravenous contrast agent. * History of nephrotic range proteinuria. * Known history of allergy to soy beans or peanuts, immunoglobulin A (IgA) deficiency, antibodies to IgA , or hypersensitivity to CSL112 or any of its components. * Other severe comorbid condition, concurrent medication, or other issue that renders the subject unsuitable for participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With at Least One Occurrence of Treatment-emergent Renal Serious Adverse Events (SAEs) (SAF) | Up to 9 weeks | A renal SAE is defined as any SAE with a MedDRA preferred term included in the Acute Renal Failure narrow Standard MedDRA Query or a preferred term of renal tubular necrosis, renal cortical necrosis, renal necrosis, or renal papillary necrosis. |
| Percent of Participants With Treatment-emergent Acute Kidney Injury (AKI ) | Up to 4 weeks | Acute kidney injury is defined as an absolute increase in serum creatinine from baseline ≥ 0.3 mg/dL during the Active Treatment Period that is sustained upon repeat measurement by the central laboratory no earlier than 24 hours after the elevated value. If no repeat value is obtained, a single serum creatinine value that is increased from baseline ≥ 0.3 mg/dL (26.5 μmol/L) during the Active Treatment Period would also fulfil the definition of AKI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of TEAEs | Up to 9 weeks | — |
| Number of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | Up to 9 weeks | Adverse drug reactions or suspected adverse drug reactions are defined as: 1. All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or 2. Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or 3. All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or 4. All TEAEs for which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more. |
| Percentage of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | Up to 9 weeks | Adverse drug reactions or suspected adverse drug reactions are defined as: 1. All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or 2. Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or 3. All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or 4. All TEAEs for which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more. |
| Number of Participants With Change in Renal Status | Baseline and up to 4 weeks | Number of participants with changes in renal status defined as: * Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. \> 0 to \< 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. \> 0.5 mg/dL * Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL * Initiation of renal replacement therapy * Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit |
| Percentage of Participants With Change in Renal Status | Baseline and up to 4 weeks | Percentage of participants with changes in renal status defined as: * Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. \> 0 to \< 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. \> 0.5 mg/dL * Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL * Initiation of renal replacement therapy * Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit |
| Number of Participants With Change in Hepatic Status | Baseline and up to 4 weeks | Number of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: 1. Alanine aminotransferase (ALT) \> 3 x upper limit of normal (ULN) 2. ALT \> 5 x ULN 3. ALT \> 10 x ULN 4. Serum total bilirubin \> 1.5 x ULN 5. Serum total bilirubin \> 2 x ULN 6. Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009). |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Up to 9 weeks | — |
| Number of Participants With Treatment-emergent Bleeding Events | Up to 9 weeks | Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011). |
| Percentage of Participants With Treatment-emergent Bleeding Events | Up to 9 weeks | Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011). |
| Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112 | Up to 9 weeks | — |
| Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC | Immediately after end of infusion | — |
| Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC | Immediately after end of infusion | — |
| Plasma apoA-I and Phosphatidylcholine (PC) Accumulation Ratio After Infusion 4 | Immediately after end of infusion | The plasma apoA-I and PC accumulation ratio will be determined for CSL112-treated subjects. |
| Percentage of Participants With Change in Hepatic Status | Baseline and up to 4 weeks | Percentage of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: 1. Alanine aminotransferase (ALT) \> 3 x upper limit of normal (ULN) 2. ALT \> 5 x ULN 3. ALT \> 10 x ULN 4. Serum total bilirubin \> 1.5 x ULN 5. Serum total bilirubin \> 2 x ULN 6. Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009). |
| Percentage of Participants With TEAEs | Up to 9 weeks | — |
Countries
Germany, Hungary, Israel, Netherlands, United States
Participant flow
Pre-assignment details
To ensure that at least 1/3 of the study population had an estimated glomerular filtration (eGFR) in the chronic kidney disease (CKD) Stage 3b range, no more than 2/3 of the study population were to have an eGFR in the CKD Stage 3a range. Randomization was stratified by eGFR and by medical history of diabetes.
Participants by arm
| Arm | Count |
|---|---|
| CSL_112 CSL112 will be administered intravenously, once weekly for 4 consecutive weeks (4 infusions in total).
CSL\_112: CSL112 is a novel formulation of apolipoprotein A-I (apoA-I) purified from human plasma and reconstituted to form high-density lipoprotein (HDL) particles. | 55 |
| Placebo Placebo will be administered at the same frequency, volume and duration as the CSL112 infusion.
Placebo: 0.9% weight/volume sodium chloride solution (ie, normal saline) | 28 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Moved to another town | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | CSL_112 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 70.6 years STANDARD_DEVIATION 10.95 | 71.9 years STANDARD_DEVIATION 10.12 | 71.1 years STANDARD_DEVIATION 10.63 |
| Age, Customized 18-64 years | 11 Participants | 4 Participants | 15 Participants |
| Age, Customized 65-84 years | 42 Participants | 23 Participants | 65 Participants |
| Age, Customized 85 years and over | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 52 Participants | 28 Participants | 80 Participants |
| Region of Enrollment Germany | 12 Participants | 4 Participants | 16 Participants |
| Region of Enrollment Hungary | 20 Participants | 8 Participants | 28 Participants |
| Region of Enrollment Israel | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment Netherlands | 8 Participants | 2 Participants | 10 Participants |
| Region of Enrollment United States | 10 Participants | 9 Participants | 19 Participants |
| Sex: Female, Male Female | 18 Participants | 10 Participants | 28 Participants |
| Sex: Female, Male Male | 37 Participants | 18 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 52 | 2 / 28 |
| other Total, other adverse events | 18 / 52 | 12 / 28 |
| serious Total, serious adverse events | 12 / 52 | 10 / 28 |
Outcome results
Primary
Percent of Participants With at Least One Occurrence of Treatment-emergent Renal Serious Adverse Events (SAEs) (SAF)
A renal SAE is defined as any SAE with a MedDRA preferred term included in the Acute Renal Failure narrow Standard MedDRA Query or a preferred term of renal tubular necrosis, renal cortical necrosis, renal necrosis, or renal papillary necrosis.
Time frame: Up to 9 weeks
Population: The Safety (SAF) Population consisted of all subjects who received at least a partial dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Percent of Participants With at Least One Occurrence of Treatment-emergent Renal Serious Adverse Events (SAEs) (SAF) | 1.9 percentage of participants |
| Placebo | Percent of Participants With at Least One Occurrence of Treatment-emergent Renal Serious Adverse Events (SAEs) (SAF) | 14.3 percentage of participants |
95% CI: [-0.296, -0.005]Newcombe-Wilson
Primary
Percent of Participants With Treatment-emergent Acute Kidney Injury (AKI )
Acute kidney injury is defined as an absolute increase in serum creatinine from baseline ≥ 0.3 mg/dL during the Active Treatment Period that is sustained upon repeat measurement by the central laboratory no earlier than 24 hours after the elevated value. If no repeat value is obtained, a single serum creatinine value that is increased from baseline ≥ 0.3 mg/dL (26.5 μmol/L) during the Active Treatment Period would also fulfil the definition of AKI.
Time frame: Up to 4 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Percent of Participants With Treatment-emergent Acute Kidney Injury (AKI ) | 4.0 percentage of participants |
| Placebo | Percent of Participants With Treatment-emergent Acute Kidney Injury (AKI ) | 14.3 percentage of participants |
95% CI: [-0.277, 0.025]Newcombe-Wilson
Secondary
Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC
Time frame: Immediately after end of infusion
Population: PK
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CSL_112 | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC | apoA-I | 124.6 mg/dL | Standard Deviation 25.38 |
| CSL_112 | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC | PC | 198.4 mg/dL | Standard Deviation 43.56 |
| Placebo | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC | apoA-I | -4.5 mg/dL | Standard Deviation 9.46 |
| Placebo | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 1 for apoA-I and PC | PC | -4.9 mg/dL | Standard Deviation 15.04 |
Secondary
Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC
Time frame: Immediately after end of infusion
Population: PK
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CSL_112 | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC | PC | 200.0 mg/dL | Standard Deviation 71.78 |
| CSL_112 | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC | apoA-I | 141.5 mg/dL | Standard Deviation 41.11 |
| Placebo | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC | apoA-I | 1.4 mg/dL | Standard Deviation 23.57 |
| Placebo | Baseline-corrected Plasma Concentration Maximum (Cmax) After Infusion 4 for apoA-I and PC | PC | -13.2 mg/dL | Standard Deviation 27.96 |
Secondary
Number of Participants With Change in Hepatic Status
Number of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: 1. Alanine aminotransferase (ALT) \> 3 x upper limit of normal (ULN) 2. ALT \> 5 x ULN 3. ALT \> 10 x ULN 4. Serum total bilirubin \> 1.5 x ULN 5. Serum total bilirubin \> 2 x ULN 6. Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009).
Time frame: Baseline and up to 4 weeks
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CSL_112 | Number of Participants With Change in Hepatic Status | total bilirubin > 1.5 x ULN | 4 participants |
| CSL_112 | Number of Participants With Change in Hepatic Status | total bilirubin > 2 x ULN | 1 participants |
| CSL_112 | Number of Participants With Change in Hepatic Status | ALT > 3 x ULN | 0 participants |
| CSL_112 | Number of Participants With Change in Hepatic Status | ALT > 5 x ULN | 0 participants |
| CSL_112 | Number of Participants With Change in Hepatic Status | ALT > 10 x ULN | 0 participants |
| CSL_112 | Number of Participants With Change in Hepatic Status | Possible Hy's law cases | 0 participants |
| Placebo | Number of Participants With Change in Hepatic Status | ALT > 10 x ULN | 0 participants |
| Placebo | Number of Participants With Change in Hepatic Status | total bilirubin > 1.5 x ULN | 1 participants |
| Placebo | Number of Participants With Change in Hepatic Status | ALT > 5 x ULN | 0 participants |
| Placebo | Number of Participants With Change in Hepatic Status | total bilirubin > 2 x ULN | 0 participants |
| Placebo | Number of Participants With Change in Hepatic Status | Possible Hy's law cases | 0 participants |
| Placebo | Number of Participants With Change in Hepatic Status | ALT > 3 x ULN | 0 participants |
Secondary
Number of Participants With Change in Renal Status
Number of participants with changes in renal status defined as: * Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. \> 0 to \< 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. \> 0.5 mg/dL * Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL * Initiation of renal replacement therapy * Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit
Time frame: Baseline and up to 4 weeks
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CSL_112 | Number of Participants With Change in Renal Status | ≤ baseline value | 9 participants |
| CSL_112 | Number of Participants With Change in Renal Status | > 0 to < 0.3 mg/dL | 35 participants |
| CSL_112 | Number of Participants With Change in Renal Status | ≥ 0.3 to ≤ 0.5 mg/dL | 4 participants |
| CSL_112 | Number of Participants With Change in Renal Status | > 0.5 mg/dL | 2 participants |
| CSL_112 | Number of Participants With Change in Renal Status | ≥ 1.5 × Baseline | 1 participants |
| CSL_112 | Number of Participants With Change in Renal Status | ≥ 2 × Baseline | 0 participants |
| CSL_112 | Number of Participants With Change in Renal Status | ≥ 3 × Baseline | 0 participants |
| CSL_112 | Number of Participants With Change in Renal Status | ≥ 4.0 mg/dL | 0 participants |
| CSL_112 | Number of Participants With Change in Renal Status | Decrease in eGFR by ≥ 25% | 5 participants |
| CSL_112 | Number of Participants With Change in Renal Status | Initiation of renal replacement therapy | 0 participants |
| Placebo | Number of Participants With Change in Renal Status | ≥ 4.0 mg/dL | 0 participants |
| Placebo | Number of Participants With Change in Renal Status | ≤ baseline value | 3 participants |
| Placebo | Number of Participants With Change in Renal Status | ≥ 2 × Baseline | 0 participants |
| Placebo | Number of Participants With Change in Renal Status | > 0 to < 0.3 mg/dL | 18 participants |
| Placebo | Number of Participants With Change in Renal Status | Initiation of renal replacement therapy | 1 participants |
| Placebo | Number of Participants With Change in Renal Status | ≥ 0.3 to ≤ 0.5 mg/dL | 4 participants |
| Placebo | Number of Participants With Change in Renal Status | ≥ 3 × Baseline | 0 participants |
| Placebo | Number of Participants With Change in Renal Status | > 0.5 mg/dL | 2 participants |
| Placebo | Number of Participants With Change in Renal Status | Decrease in eGFR by ≥ 25% | 4 participants |
| Placebo | Number of Participants With Change in Renal Status | ≥ 1.5 × Baseline | 0 participants |
Secondary
Number of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR
Adverse drug reactions or suspected adverse drug reactions are defined as: 1. All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or 2. Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or 3. All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or 4. All TEAEs for which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more.
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Number of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | 30 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | 4 participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 38 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 20 participants |
Secondary
Number of Participants With Treatment-emergent Bleeding Events
Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011).
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Number of Participants With Treatment-emergent Bleeding Events | 7 participants |
| Placebo | Number of Participants With Treatment-emergent Bleeding Events | 5 participants |
Secondary
Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CSL_112 | Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112 | CSL112 antibody | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112 | apoA-I antibody | 0 percentage of participants |
| Placebo | Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112 | CSL112 antibody | 0 percentage of participants |
| Placebo | Percentage of Participants With Binding Antibodies Specific to Apolipoprotein A-I (Apo-A1) and CSL112 | apoA-I antibody | 0 percentage of participants |
Secondary
Percentage of Participants With Change in Hepatic Status
Percentage of participants with a change from baseline in hepatic status and that is sustained for ≥ 24 hours upon repeat measurement, defined as: 1. Alanine aminotransferase (ALT) \> 3 x upper limit of normal (ULN) 2. ALT \> 5 x ULN 3. ALT \> 10 x ULN 4. Serum total bilirubin \> 1.5 x ULN 5. Serum total bilirubin \> 2 x ULN 6. Possible Hy's law cases, as defined in the FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009).
Time frame: Baseline and up to 4 weeks
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CSL_112 | Percentage of Participants With Change in Hepatic Status | ALT > 10 x ULN | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Hepatic Status | total bilirubin > 2 x ULN | 1.9 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Hepatic Status | ALT > 5 x ULN | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Hepatic Status | Possible Hy's law cases | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Hepatic Status | ALT > 3 x ULN | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Hepatic Status | total bilirubin > 1.5 x ULN | 7.7 percentage of participants |
| Placebo | Percentage of Participants With Change in Hepatic Status | ALT > 3 x ULN | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Hepatic Status | total bilirubin > 1.5 x ULN | 3.7 percentage of participants |
| Placebo | Percentage of Participants With Change in Hepatic Status | Possible Hy's law cases | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Hepatic Status | total bilirubin > 2 x ULN | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Hepatic Status | ALT > 5 x ULN | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Hepatic Status | ALT > 10 x ULN | 0 percentage of participants |
Secondary
Percentage of Participants With Change in Renal Status
Percentage of participants with changes in renal status defined as: * Absolute increases from baseline in serum creatinine as follows: i. ≤ baseline value ii. \> 0 to \< 0.3 mg/dL iii. ≥ 0.3 to ≤ 0.5 mg/dL iv. \> 0.5 mg/dL * Increases in serum creatinine that are sustained for ≥ 24 hours upon repeat measurement that are greater than or equal to 1.5 x, 2 x, or 3.0 x the baseline value, or serum creatinine ≥ 4.0 mg/dL * Initiation of renal replacement therapy * Decrease in eGFR ≥ 25% from baseline starting during the active treatment period and that is sustained at the final study visit
Time frame: Baseline and up to 4 weeks
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CSL_112 | Percentage of Participants With Change in Renal Status | ≤ Baseline Value | 17.3 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | > 0 to < 0.3 mg/dL | 67.3 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | ≥ 0.3 to ≤ 0.5 mg/dL | 7.7 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | > 0.5 mg/dL | 3.8 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | ≥ 1.5 × Baseline | 1.9 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | ≥ 2 × Baseline | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | ≥ 3 × Baseline | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | ≥ 4.0 mg/dL | 0 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | Decrease in eGFR by ≥ 25% | 9.6 percentage of participants |
| CSL_112 | Percentage of Participants With Change in Renal Status | Initiation of renal replacement therapy | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | Initiation of renal replacement therapy | 3.6 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | ≤ Baseline Value | 10.7 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | ≥ 2 × Baseline | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | > 0 to < 0.3 mg/dL | 64.3 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | Decrease in eGFR by ≥ 25% | 14.3 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | ≥ 0.3 to ≤ 0.5 mg/dL | 14.3 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | ≥ 3 × Baseline | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | > 0.5 mg/dL | 7.1 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | ≥ 4.0 mg/dL | 0 percentage of participants |
| Placebo | Percentage of Participants With Change in Renal Status | ≥ 1.5 × Baseline | 0 percentage of participants |
Secondary
Percentage of Participants With TEAEs
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Percentage of Participants With TEAEs | 73.1 percentage of participants |
| Placebo | Percentage of Participants With TEAEs | 71.4 percentage of participants |
Secondary
Percentage of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR
Adverse drug reactions or suspected adverse drug reactions are defined as: 1. All TEAEs, including local tolerability events, that begin during or within 1 hour after the end of an infusion; or 2. Those TEAEs that the investigator or sponsor indicate may be causally related to product administration; or 3. All TEAEs for which the Investigator's causality assessment is missing or indeterminate; or 4. All TEAEs for which the incidence in an active treatment arm exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more, provided the difference in incidence rates is 1% or more.
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Percentage of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | 57.7 percentage of participants |
| Placebo | Percentage of Participants With Treatment-emergent Adverse Drug Reaction (ADR) or Suspected ADR | 14.3 percentage of participants |
Secondary
Percentage of Participants With Treatment-emergent Bleeding Events
Bleeding events are as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al., 2011).
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Percentage of Participants With Treatment-emergent Bleeding Events | 13.5 percentage of participants |
| Placebo | Percentage of Participants With Treatment-emergent Bleeding Events | 17.9 percentage of participants |
Secondary
Plasma apoA-I and Phosphatidylcholine (PC) Accumulation Ratio After Infusion 4
The plasma apoA-I and PC accumulation ratio will be determined for CSL112-treated subjects.
Time frame: Immediately after end of infusion
Population: Pharmacokinetic Population (PK) consists of all subjects in the SAF who had at least 1 measurable plasma concentration of either apoA-I or PC.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CSL_112 | Plasma apoA-I and Phosphatidylcholine (PC) Accumulation Ratio After Infusion 4 | apoA-I | 1.2 mg/dL | Standard Deviation 0.32 |
| CSL_112 | Plasma apoA-I and Phosphatidylcholine (PC) Accumulation Ratio After Infusion 4 | PC | 1.0 mg/dL | Standard Deviation 0.36 |
Secondary
Total Number of TEAEs
Time frame: Up to 9 weeks
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL_112 | Total Number of TEAEs | 111 Number of TEAEs |
| Placebo | Total Number of TEAEs | 61 Number of TEAEs |